Each year, 700,000 - 900,000 burn patients develop severe hypertrophic scarring (HS). These scars restrict movement, are painful, and severely limit the quality of life for these patients. Our group has recently observed that propranolol (PPL), a non-specific 1, 2adrenergic receptor (-AR) antagonist, improves wound healing (WH) and reduces HS in severely burned children. Preliminary experiments demonstrate that burn injury not only drastically elevates catecholamine levels in the skin, but also alters the expression of 2-ARs in the scar, and leads to changes in 1- and 2-AR mediated signaling in fibroblasts from HS. Importantly, PPL attenuates these changes. The effects of chronic catecholamine exposure or long-term -blockade on scarring in the severely burned have also not been studied. The overarching hypothesis of this project is therefore that delayed WH and severe HS result from chronic stimulation by catecholamines that disrupt normal -AR expression and function, and that -blockade improves WH and decreases HS by correcting these catecholamine-induced deficits. We propose that impaired WH related to chronic catecholamine exposure is due to heightened inflammation in the wound and scar, and that defects in -AR signaling lead to increased fibrosis (characterized by greater deposition of keratin and collagen), resulting in severe HS. We further hypothesize that long-term -blockade decreases local inflammation and restores -AR signaling, improving WH and reducing HS. To test this hypothesis, we will by pursuing three Specific Aims investigate the molecular events occurring in the skin and scars of the severely burned treated with and without propranolol in two placebo-controlled trials of PPL use to reduce the post-burn hypermetabolic response. Aim 1 is to determine the effects of chronic catecholamine exposure and -blockade on WH and HS by measuring tissue catecholamine levels, wound healing, scar severity, range of motion, and genetic polymorphisms related to the response to -blockade. Patients will receive either short- or long-term -blockade to determine which results in better clinical outcomes. Aim 2 is to quantitate the effects of -blockade on scar composition, by determining cellular composition and -AR expression in the wound and scar, utilizing innovative metabolic tracer studies to measure real-time collagen and keratin turnover rates, and measure pro-and anti-fibrotic factors that regulate fibrosis. Aim 3 is to determine the effects of -blockade on -AR expression, activity, and binding partners in dermal fibroblasts from HS and the same patients' non-burned skin. We will use primary cell cultures to study cellular signaling responses after stimulation wit catecholamines or -blockade with 1- and2-specific antagonists, in addition to PPL. Development of a therapy to improve post-burn wound healing and decrease scarring would improve the quality of life for severely burned patients and reduce the long-term cost of their surgical and psychological care. Therefore, determining whether long-term mitigation of catecholamine-triggered -AR signaling improves WH and reduces HS in severely burned patients is a high priority.